© 1996 American Heart Association, Inc.
Articles |
Analysis of Heart-Infiltrating T-Cell Clonotypes in Experimental Autoimmune Myocarditis in Rats
From the Department of Immunology (H.H., T. Inomata, H.S., T.A.) and the First Department of Internal Medicine (H.H., T. Inomata, T. Izumi, A.S.), Niigata (Japan) University School of Medicine.
Correspondence to Haruo Hanawa, MD, the First Department of Internal Medicine, Niigata University School of Medicine, Niigata 951, Japan.
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Abstract |
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 Top Abstract IntroductionMaterials and Methods Results Discussion References |
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Abstract Experimental autoimmune myocarditis (EAM) resembles the lethal giant cell myocarditis seen in humans, and the recurrent forms lead to dilated cardiomyopathy (DCM). EAM in rats induced by a subcutaneous injection of cardiac myosin has been shown to be a T cell–mediated autoimmune disease.
ß T cells
have proved to be important by the observation that antibodies to
ß T-cell receptor (TCR) prevent disease progression. ß T
cells recognize antigenic peptides bound to major histocompatibility
(MHC) molecules by ß TCR, and complementarity determining region 3
(CDR3) is considered the most important region for antigen recognition.
To elucidate the nature of this T cell–mediated myocarditis, we
analyzed TCR Vß chains of heart-infiltrating T cells. In
the early stage of EAM, none of 22 TCR Vß chain transcripts seemed to
be dominant by reverse transcription–polymerase chain reaction
analysis of total RNA and flow cytometric analysis. On
the other hand, single-strand conformation polymorphism
analysis of TCR Vß8.2, Vß8.5, Vß10, and Vß16 cDNA
amplified by polymerase chain reaction encompassing the CDR3 revealed
oligoclonal expansion in heart-infiltrating T cells isolated from
animals at various disease stages. cDNA encoding Vß CDR3 from
heart-infiltrating and pericardial effusion T cells in rats with
EAM revealed more restricted sequences than did cells from rats with
normal spleens. Clones from distinct lesions of the same animal were
identical, and clones from heart-infiltrating and pericardial
effusion T cells from the same animal showed overlap. Thus, CDR3 of the
TCR ß chain may be important in rat EAM, and heart-infiltrating T
cells are considered to recognize the specific antigen.
Key Words: autoimmune myocarditis • dilated cardiomyopathy • complementarity-determining region 3 • T-cell receptor
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Experimental autoimmune myocarditis (EAM) is induced by injecting cardiac myosin into susceptible strains of rats1 and mice.2 Lewis rats develop myocarditis 14 days after injection of cardiac whole myosin or rod myosin. EAM in Lewis rats is characterized by cardiomegaly, pericardial effusion, and extensive myocardial necrosis as well as by massive infiltration of MNCs into the heart; some animals die of congestive heart failure. This model, which resembles lethal giant cell myocarditis in humans,3 was recently shown to develop recurrent episodes leading to DCM.4 EAM has been shown to be a T cell–mediated autoimmune disease by adoptive transfer.5 6 Because antibodies to the
ß TCR
prevent
the progression of myocarditis,7 ß T cells are
considered to play an important role in the disease.
Heart-infiltrating and pericardial space–infiltrating ß T
cells are predominantly CD4+.8 Given that
cardiac myosin–MHC class II complexes are present on resident
antigen-presenting cells in the normal mouse
heart,9 self-reactive T cells may recognize these
antigen-presenting cells and trigger myocarditis in cardiac
myosin–induced EAM.
ß T cells recognize antigenic peptides in the context of MHC as a
result of interaction of the peptide-MHC complex with the and ß
chains.10 As is the case for immunoglobulins, the regions
equivalent to CDR1 and CDR2 in TCR are encoded within the V gene
itself, whereas the CDR3-equivalent region is formed by the conjunction
of V and J (in TCR or 
) or by V, D, and J (in TCR ß and 
).
CDR3 is considered the most important region for antigen recognition.
Recently, several studies of animal models and human disease have
examined TCR V gene
expression11 12 13 14 15
and CDR3
sequences16 17 18 19 20 21
of infiltrating T cells. Seko et
al22 analyzed the expression of TCR Vß genes in
infiltrating cells in the heart with acute myocarditis caused by
coxsackievirus B3. In mouse and rat EAM, the expression of TCR Vß
genes and CDR3 sequences in heart-infiltrating T cells has not been
reported. In the present study, we analyzed
heart-infiltrating T-cell clonotypes in Lewis rat EAM.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Animals
Lewis rats were obtained from Charles River, Japan (Atsugi, Kanagawa, Japan) and were maintained in our animal facilities until 6 weeks of age.
Purification of Porcine Rod Cardiac Myosin
Whole cardiac
myosin was prepared from the
ventricular muscle of porcine hearts as previously
described1 and was then digested with -chymotrypsin
at 20°C for 16 minutes in 0.12 mmol/L NaCl, 20 mmol/L imidazole-HCl
(pH 7.0), and 1 mmol/L EDTA at an enzyme-to-substrate ratio of
1:200 (wt/wt). The preparation was then centrifuged at
100 000g for 1 hour. The pellet was dissolved in buffer A
(0.6 mol/L NaCl and 50 mmol/L imidazole-HCl [pH 7.0]) and then mixed
with 3 vol ice-cold ethanol. After centrifugation
at 9000g for 10 minutes, the pellet was dissolved in and
dialyzed against buffer A. The solution was then centrifuged at
100 000g for 1 hour, and the supernatant was collected and
used as rod cardiac myosin.23
Induction of EAM
On day 0, Lewis rats were injected
subcutaneously in the
footpads with 0.3 mg of porcine rod cardiac myosin in complete
Freund's adjuvant supplemented with Mycobacterium
tuberculosis at a concentration of 10 mg/mL.
Cell Preparation
Lymph node MNCs, spleen MNCs, and
heart-infiltrating MNCs
were isolated by forcing popliteal lymph node, spleen, and heart
(digested with 0.015% trypsin and 0.015% collagenase for
15 minutes in MEM supplemented with 7.5 mmol/L HEPES and 2% newborn
calf serum) through a 200-gauge stainless steel mesh. Red blood cells
in the spleen cell preparation were lysed in 0.17 mol/L Tris
supplemented with 0.83% NH4Cl. The heart cell preparation
was washed with supplemented MEM, and MNCs were purified by passage
through a column of glass wool (a 20-mL column packed with 0.8 g of
glass wool). MNCs in peripheral blood were isolated by
Ficoll-Faque (Pharmacia) density gradient
centrifugation at 1000g for 20 minutes. MNCs
in pericardial effusion were analyzed after hemolysis in 0.17
mol/L Tris supplemented with 0.83% NH4Cl.
RT-PCR Analysis of Vß Expression
Total RNA was isolated
from heart and from spleen MNCs by
acid guanidium thiocyanate–phenol–chloroform extraction. cDNA
was synthesized from 10 µg of total RNA with a TCR Cß
primer24 and murine Moloney leukemia virus reverse
transcriptase (GIBCO-BRL) in a final volume of 20 µL. Heart and
spleen Vß-specific PCR products were generated with AmpliTaq
polymerase (Toyobo), 22 Vß-specific primers,24 and
the same Cß primer from 5 µL of heart cDNA and 0.2 µL of spleen
cDNA, according to the following amplification profile: 30 cycles at
94°C for 60 seconds, 55°C for 90 seconds, and 72°C for 120
seconds. Amplified products were separated on 3% agarose gels and
stained with ethidium bromide.
Flow Cytometry Analysis
The surface phenotype of fresh viable
cells was
determined by using monoclonal antibodies with two-color
immunofluorescence. For detecting the expression of
ß TCR versus Vß8.2, Vß8.5, Vß10, and Vß16, MNCs were
incubated first with unconjugated monoclonal antibodies to Vß8.2
(R78), Vß8.5 (B73), Vß10 (G101), or Vß16 (HIS42) (Pharmingen) and
then, after washing, with phycoerythrin-conjugated antibodies to
mouse IgG antibody (Vector Laboratories). After incubation with normal
mouse serum, the cells were exposed to fluorescein
isothiocyanate–conjugated mouse monoclonal antibody to ß TCR
(R73) (Serotec). Stained cells (1x104) were then
analyzed with a FACScan flow cytometer (Becton Dickinson).
PCR-SSCP Analysis
Amplified PCR products were diluted (2:3)
in denaturing
solution (95% formamide, 10 mmol/L EDTA, 0.1% bromphenol blue, and
0.1% xylene cyanol), heated at 96°C for 5 minutes, and then cooled
on ice for 10 minutes. The diluted sample (10 µL) was adjusted to
50% glycerol, and 3 µL was subjected to SSCP analysis by
electrophoresis on nondenaturing 5% polyacrylamide (ratio of
acrylamide to bisacrylamide, 19:1) gels
(14x14x0.1 cm) in 0.5x Tris-borate-EDTA containing 10%
glycerol
at 14 V/cm for 5 hours at room temperature. DNA fragments were detected
with a silver staining kit (Daiichi).25
Sequencing Analysis
For the purposes of cloning and
sequencing,
Vß-specific PCR products were purified with SUPREC-02
(Takara) and directly inserted into the pGEM-T vector (Promega). The
recombinant plasmids were then used to transform Escherichia
coli JM109 competent cells (Takara). Individual
ampicillin-resistant colonies were isolated, and the
plasmid DNA was sequenced with a TaqDyeDeoxy terminator
cycle sequencing kit and a DNA sequencer (model 373A, Applied
Biosystems).
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Results |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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RT-PCR Analysis of TCR Vß Expression
Rats injected once with porcine rod cardiac myosin developed acute myocarditis 14 days later. Because a marked bias toward the expression of Vß8.2 was apparent early during the onset of EAE induced by guinea pig MBP in Lewis rats,11 26 we compared TCR Vß expression in the heart of two individual rats with myocarditis on day 14 (early stage) with that on MNCs from normal spleen. The hearts of two EAM rats killed on day 14 exhibited spotty macroscopic white lesions, from which RNA was extracted. PCR analysis revealed that the expression of 22 Vß genes in the hearts of individual EAM rats was similar to that apparent in normal spleen (Fig 1
).
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X174 Hae III indicates an Hae III digest of
Flow Cytometry Analysis of Vß8.2, Vß8.5, Vß10, and
Vß16 Expression of MNCs From Normal and EAM Rats
We also examined
TCR Vß expression by flow cytometry. All
samples from two individual EAM rats and a normal rat were
analyzed. Consistent with the RT-PCR results,
two-color staining of ß TCR plus Vß8.2, Vß8.5, Vß10, or
Vß16 revealed that the expression of these Vß chains on ß T
cells from spleen, peripheral blood, lymph node, and heart
of EAM rats on day 14 was indistinguishable from that apparent on
ß T cells from normal rats (Fig 2). ß T cells
expressing Vß8.2, Vß8.5, Vß10, or Vß16 constituted
approximately one fourth of all ß T cells from the heart of EAM
rats on day 14.
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PCR-SSCP Analysis of TCR ß Chain CDR3
We examined the
structure of PCR products corresponding to the
CDR3 region of the TCR ß chain by SSCP analysis.
Heterogeneous PCR products corresponding to this region
migrate as a smear on SSCP analysis, whereas
homogeneous products migrate as bands.27
PCR products corresponding to Vß8.2, Vß8.5, Vß10, and Vß16
from normal spleen and from individual EAM heart on day 14, 16, or 19
migrated as a single band on ethidium bromide–stained agarose gels
(Fig 3). However, on SSCP analysis, PCR
products from normal spleen produced a smear, whereas those from
EAM heart generated bands within a smear (Fig 3). These results
show
that TCR Vß8.2, Vß8.5, Vß10, and Vß16 cDNA from EAM heart was
derived from oligoclonal ß T cells. The positions of the bands in
the smear of PCR products from EAM heart differed among the three
time points, suggesting that the ß T-cell clones varied with the
stage of disease.
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Sequence Analysis of TCR ß Chain CDR3
CDR3 sequences of
Vß8.2, Vß8.5, Vß10, and Vß16 cDNA from
normal spleen did not reveal oligoclonal expansion (Fig 4). In
contrast, the corresponding CDR3 sequences of
cDNA for EAM heart on days 14, 16, and 19 revealed clonal expansion at
each stage (Fig 5).
For example, 11 of 14 and 2 of 14 Vß8.2 cDNA CDR3 sequences from EAM
heart on day 14 were identical. However, except for one common Vß8.2
cDNA clone detected on days 14 and 19, the cDNA clones differed at each
time point, consistent with the results of the PCR-SSCP
analysis. Fig 6 shows CDR3 sequences of Vß8.2
cDNA clones from another gross lesion of the same EAM heart on day 14;
the sequences were the same as the two shown in Fig 5A,
suggesting that
the same clones expanded in each heart lesion of individual animals.
The EAM rat whose heart was examined on day 16 showed moderate
pericardial effusion; the CDR3 sequences of Vß8.2, Vß8.5, Vß10,
and Vß16 cDNA from MNCs in the pericardial effusion showed an overlap
with those from the corresponding rat heart (Fig
7).
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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We have determined the clonotypes of heart-infiltrating
ß
T cells in EAM induced by porcine rod cardiac myosin, because these
cells were thought to play an important role in this disease. In the
present study, CDR3 of the TCR ß chain was important in rat EAM.
Because CDR3 is the most important region for recognizing the antigen
peptide, this finding shows that heart-infiltrating T cells are
considered to recognize the specific antigen.
The etiology of DCM remains enigmatic, but the most widely accepted
hypothesis is that DCM is initiated by a viral infection and
perpetuated by immune factors.29 DCM is thought to be, at
least in part, somewhat of an autoimmune disease.30
Anti-heart antibodies have been detected in individuals with
DCM.31 Carlquist et al32 verified HLA-DR4
involvement in DCM. The class II MHC antigens are restriction elements
for the interaction of the CD4+ T cells with antigens. In
DCM, heart-infiltrating CD4+ ß T cells may
recognize the specific antigen in the context of MHC as a result of the
interaction of the peptide-MHC complex with the and ß chains.
Recently, rat EAM has been shown to develop into recurrent forms of
myocarditis and to lead to DCM.4 T cells with the amino
acid motif LRG in the CDR3 are found in EAE lesions in Lewis rats and
in human multiple sclerosis lesions.20 The characteristic
feature of T-cell clonotypes in rat EAM may also be applicable to human
DCM, similar to EAE and human multiple sclerosis.
Vß usage in the heart of EAM rats was similar to that in normal spleen, and none of the 22 TCR Vß chain transcripts seemed to be dominant. The V-region disease hypothesis is controversial.33 In both rats and mice, molecular analyses of the T-cell populations reactive to MBP or its encephalitogenic peptide show them to be extremely limited with respect to TCR gene usage.11 34 In contrast, in EAE induced by PLP, heterogeneous TCR Vß expression is apparent in central nervous system lesions, even when the immune response is initiated with a short peptide antigen or by a T-cell clone expressing a single TCR Vß chain.13 35 36 In murine experimental autoimmune uveitis induced by interphotoreceptor retinoid-binding proteins,12 expression of the TCR ß chain V gene is highly restricted at the site of inflammation. However, Vß gene expression is not restricted in nonobese diabetic mice.37 Thus, whether TCR ß chain V gene expression is restricted or not appears to depend on the species and the antigen of the autoimmune model.
In the present study, several T-cell clones were present
at the site of inflammation at each stage of the disease. One reason
may be that porcine rod cardiac myosin possesses several
myocarditis-inducing epitopes. Our recent studies indicate the
presence of several myocarditogenic epitopes in porcine rod cardiac
myosin,23 and Wegmann et al38 identified
several such epitopes in rat cardiac -myosin heavy chain. In
EAE, both MBP and PLP have several encephalitogenic epitopes. For
example, both PLP-(178 to 191) and PLP-(139 to 151) peptides induce
EAE, with the onset of disease being earlier for PLP-(178 to
191).39
In autoimmune diseases, T-cell clones responding to self peptides are thought to rearrange early during development and to fail to add nucleotides because of a lack of terminal deoxynucleotidyl transferase, as well as having a paucity of N-region nucleotide additions.40 N-region nucleotide additions are the random addition of nucleotides between the V, D, and J gene segments.10 Vß8.2, Vß8.5, Vß10, and Vß16 cDNA clones from normal spleen showed 1 to 16 N-region nucleotide additions (5.8±3.4 [mean±SD]), whereas those from heart or the pericardial space of EAM rats showed 1 to 20 N-region nucleotide additions (5.7±2.8). Thus, T-cell clones from inflammatory lesions showed the same number of N-region nucleotide additions as normal spleen.
A previous study showed that MNCs in pericardial effusion probably infiltrate the outer layer of the heart.8 The similarity of T-cell clonotypes in heart and pericardial effusion supports this conclusion. Clinically, myocarditis is usually accompanied by pericarditis and pericardial effusion. Clonotypes of MNCs in pericardial effusion could be sufficiently analyzed as synovial fluid cells in rheumatoid arthritis.
In conclusion, heart-infiltrating T cells in Lewis rat EAM induced by porcine rod cardiac myosin did not seem to show restricted TCR Vß usage; however, they did show restricted CDR3 sequences of the TCR ß chain. Thus, the study of the ß chain CDR3 region is informative in rat EAM.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from the Study Group of Molecular Cardiology and grants-in-aid from the Niigata University Science Foundation and the Tsukada Medical Science Foundation.
Received June 15, 1995; accepted September 12, 1995.
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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